EP0090275B1 - Isoxazole (5,4-b) Pyridine - Google Patents

Isoxazole (5,4-b) Pyridine Download PDF

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Publication number
EP0090275B1
EP0090275B1 EP83102648A EP83102648A EP0090275B1 EP 0090275 B1 EP0090275 B1 EP 0090275B1 EP 83102648 A EP83102648 A EP 83102648A EP 83102648 A EP83102648 A EP 83102648A EP 0090275 B1 EP0090275 B1 EP 0090275B1
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EP
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Prior art keywords
compound
alkyl
formula
nitrogen
solvent
Prior art date
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Expired
Application number
EP83102648A
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English (en)
French (fr)
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EP0090275A2 (de
EP0090275A3 (en
Inventor
Giorgio Winters
Alberto Sala
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Gruppo Lepetit SpA
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Gruppo Lepetit SpA
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Priority to AT83102648T priority Critical patent/ATE30425T1/de
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Publication of EP0090275A3 publication Critical patent/EP0090275A3/en
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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
    • C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
    • C07D261/10—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D261/14—Nitrogen atoms

Definitions

  • lower alkyl represents straight or branched (C 1 ⁇ C 6 )alkyl groups such as methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert.butyl and so on;
  • lower alkoxy represents straight or branched (C l -C 6 )alkoxy groups such as methoxy, ethoxy, propoxy, iso-propoxy, n.butoxy, t.butoxy and the like;
  • lower alkanoyl represents straight or branched (C 1 ⁇ C 6 )alkanoyl groups such as acetyl, propanoyl, butanoyl and the like.
  • the general method for preparing the compounds of the invention starts from a 3-substituted 5-aminoisoxazole I which is reacted with a cyclic ketone II to form a 3,4-disubstituted 5-aminoisoxazole III.
  • R, R 1 and R 2 have the above mentioned significances.
  • the reaction is best carried out in a lower carboxylic acid, preferably acetic acid as a solvent, at a temperature ranging between room temperature and the boiling temperature of the solvent, preferably at 40-70°C.
  • the molar ratio between the two reactants varies depending on the nature of the reactants. It was found that usually an excess over 1 mole of the cyclic ketone per mole of isoxazole, up to 3 moles, gives good results.
  • the reaction time may vary within wide ranges and depends largely on the used temperature. In some cases 3-4 hours are sufficient to have a complete reaction, while sometimes a time of 24-36 hours may be appropriate.
  • R, R, and R 2 have the above mentioned meanings.
  • R 3 only represents hydrogen, lower alkyl, hydroxy-lower alkyl and benzyl.
  • III into V is best carried out by heating III with the lower alkyl isocyanate using as a solvent a tertiary base, such as triethylamine or pyridine, at the boiling temperature of the solvent for 1-6 hours.
  • a tertiary base such as triethylamine or pyridine
  • compound V is first treated with sodium hydride in an anhydrous solvent, thus obtaining the sodium salt, which is heated in the same solvent at 40-80°C for 1-3 hours.
  • the compounds VI and VII are formed in variable mutual ratio depending on the reaction conditions. By selecting case by case the most appropriate reaction conditions it is largely possible to pilot the reaction toward the preferential formation of VI or VII.
  • compound VI or compound VII or their mixtures, in which R 3 is a hydroxy-lower alkyl group are dissolved or suspended in a suitable organic solvent such as, for instance, a C l -C 4 halogenated hydrocarbon and a molar excess of a halogenating agent, preferably from about 1 to about 3 molar equivalents, are added.
  • a suitable organic solvent such as, for instance, a C l -C 4 halogenated hydrocarbon and a molar excess of a halogenating agent, preferably from about 1 to about 3 molar equivalents
  • amino-lower alkyl derivatives are then prepared by obvious procedure, for instance by treating the chloroalkyl derivative with a base under conditions which are generally known to all those skilled in the art and which will be apparent from the appended examples.
  • the compounds of the invention possess interesting CNS-depressant, anti-anxiety and antiinflammatory activity. Moreover, they display a considerably low toxicity as, generally, their LD so values are higher than 500 mg/kg when given intraperitoneally and rarely lower than 100 mg/kg. when given orally to mice.
  • the CNS-depressant activity was investigated by means of the general psychophysic screening method, as described by S. Irwin in Psychopharmacologia (Berl.) 13, 222-257, 1968. In particular, some representative experiments carried out on mice have shown that amounts from about 5 to about 100 mg/ kg. i.p. of the compounds were effective in inhibiting the spontaneous activity and the muscular tone, whereas amounts from about 30 to about 300 mg/kg. i.p. significantly impaired the motor cohordination and the righting reflex of the laboratory animals. It is to be noted that the above parameters are directly connected to sedative, hypnotic and myorelaxing properties.
  • the anti-anxiety activity of the compounds of the invention was investigated by means of the "pole climbing avoidance test", performed as described by G.
  • the compounds of the invention may be administered by different routes. While the preferred routes of administration are oral and rectal, parenteral administration can also be employed.
  • oral administration the compounds are compounded into pharmaceutical dosage forms, such as, for instance, tablets, capsules, elixirs, solutions and the like.
  • the dosage unit may contain the usual excipients, e.g. starch, gums, fatty acids, alcohols, sugars, etc.
  • rectal administration the compounds are administered in the form of suppositories, admixed with conventional vehicles, such as, for example, cocoa butter, wax, spermaceti or polyoxyethyleneglycols and their derivatives.
  • the dosage range is from about 0.05 to about 2.00 g. per day, preferably administered in divided dose.
  • the present invention provides a therapeutic composition
  • a therapeutic composition comprising as the active ingredient a compound of the invention together with a pharmaceutically acceptable carrier.
  • the organic layer is separated, the aqueous layer is washed with methylene chloride and the combined organic solutions are washed with water to neutral reaction.
  • the solvent is evaporated in vacuo.
  • the formed isomeric mixture (26 g.) is separated by chromatography on silica gel (400 g.) eluting with methylene chloride and ethyl acetate.
  • the less polar product i.e. the 5-propoxy derivative, crystallized from ethyl ether/hexane, has m.p. 97-98°C. Yield 12.3 g.
  • the more polar product, i.e. the 4-propyl derivative, crystallized from ethyl ether/hexane has m.p. 82-83°C. Yield 11.8 g.
  • Example 24 For a better illustration of possible variations of the procedure Example 24 is hereinafter described in full.
  • a stirred suspension of 20.4 g of 6,7,8,9-tetrahydro-1-methylisoxazole-[5,4-c]-isoquinoline-5(4H)-one, prepared according to Example 1b, in 550 ml of anhydrous dimethylformamide 3.3 g of a 80 percent suspension of sodium hydride are added at small portions at 20°C under nitrogen. After heating 1 hour at 70°C the mixture is cooled to 15°C and 8 ml. of 2-bromoethanol in 50 ml. of dimethylformamide are dropped in.
  • the hydrochloride prepared as usual by precipitating it from an organic solution with hydrogen chloride, when recrystallized from ethanol has m.p. 190°C (dec.).

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Neurosurgery (AREA)
  • Biomedical Technology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Neurology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)

Claims (8)

1. Isoxazol[5,4-b]pyridine der Formel
Figure imgb0036
in der R einen Alkylrest mit 1 bis 4 Kohlenstoffatomen oder eine Phenyl- oder Halogenphenylgruppe bedeutet, R1 und R2 einen Alkylenrest―(CH2)n― darstellen, in dem n eine ganze Zahl im Wert von 3 bis 5 einschließlich ist und eine der Methylengruppen durch einen Rest =NR6 ersetzt sein kann, in dem R6 einen (C1―C6)-Alkyl-, (C1―C6)Alkanoyl- oder (C1-C6)-Alkoxycarbonylrest darstellt, R3 nur einmal vorhanden ist und ein Wasserstoffatom, einen (C1―C6)-Alkyl-, Hydroxy-(C1-C6)-alkyl- oder Benzylrest, und, falls es an das heterocyclische Stickstoffatom gebunden ist, auch einen Halogen-(C1―C6)-alkyl- oder Amino-(C1-C6)-alkylrest bedeutet, in dem der Aminstickstoff dialkylsubstituiert oder in einen gesättigten heterocyclischen Ring eingeschlossen sein kann, die gestrichelte Linie anzeigt, daß eine Doppelbindung entweder zwischen dem heterocyclischen Stickstoffatom und dem Kohlenstoffatom oder zwischen dem Sauerstoff- und dem Kohlenstoffatom vorhanden ist, wobei im ersten Fall der Rest R3 an das Sauerstoffatom und im zweiten Fall an das Stickstoffatom gebunden ist.
2. Verbindung nach Anspruch 1, nämlich 7-Acetyl-5-äthoxy-6,7,8,9-tetrahydro-1-(1-methyläthyl)-isoxazolo[5,4-c][2,7]-naphthiridin.
3. Eine Verbindung der Formel
Figure imgb0037
in der R, R, und R2 wie in Anspruch 1 definiert sind.
4. Verfahren zur Herstellung einer Verbindung nach Anspruch 1, in der R, R, und R2 wie darin definiert sind und R3 nur einmal vorhanden ist, und ein Wasserstoffatom, einen (C1-C6)-Alkyl-, Hydroxy-(C1―C6)-alkyl- oder Benzylrest bedeutet, durch Erhitzen einer Verbindung der Formel
Figure imgb0038
in der R, R1 und R2 wie in Anspruch 1 definiert sind, mit einem (C1―C6)-Alkylisocyanat in einer tertiären Base bei der Siedetemperatur der Base für 1 bis 6 Stunden und Behandlung des erhaltenen Zwischenproduktes der Formel
Figure imgb0039
zunächst mit Natriumhydrid in einem wasserfreien Lösungsmittel bei Raumtemperatur, dann 1 bis 3 Stunden bei 40 bis 80°C in dem gleichen Lösungsmittel, und gewünschtenfalls mit einem Reagens, das zur Einführung des von einem Wasserstoff verschiedenen Restes R3 an das Stickstoffatom des Pyridin-Rings befähigt ist.
5. Verfahren zur Herstellung einer Verbindung nach Anspruch 1, in der R, R1 und R2 wie darin definiert sind und R3 nur einmal vorhanden ist und ein Wasserstoffatom, einen (C1―C6)-Alkyl-, Hydroxy-(C1―C6)-alkyl- oder Benzylrest bedeutet, durch Umsetzung eines 3-substituierten 5-Aminoisoxazols der Formel
Figure imgb0040
mit einem cyclischen Keton der Formel
Figure imgb0041
in einer niederen Carbonsäure als Lösungsmittel bei einer Temperatur zwischen Raumtemperatur und der Siedetemperatur des Lösungsmittels, zu einer Verbindung der Formel
Figure imgb0042
in der R, R, und R2 die in Anspruch 1 angegebenen Bedeutungen haben, die dann 1 bis 6 Stunden mit einem (C1-C6)-Alkylisocyanat in einer tertiären Base bei der Siedetemperatur der Base umgesetzt wird, und Behandeln des erhaltenen Zwischenproduktes der Formel
Figure imgb0043
zunächst mit Natriumhydrid in einem wasserfreien Lösungsmittel bei Raumtemperatur, dann 1 bis 3 Stunden bei 40 bis 80°C in dem gleichen Lösungsmittel und gewünschtenfalls mit einem Reagens, das zur Einführung des von Wasserstoff verschiedenen Restes R3 an das Stickstoffatom des Pyridin-Rings befähigt ist.
6. Verfahren zur Herstellung einer Verbindung der Formel
Figure imgb0044
in der R, R, und R2 wie in Anspruch 1 definiert sind, R3 einen Amino-(C1-C6)-alkylrest darstellt, in dem der Aminstickstoff dialkylsubstituiert oder in einen gesättigten heterocyclischen Ring eingeschlossen sein kann, durch Umsetzung einer Verbindung der Formel
Figure imgb0045
in der R4 nur einmal vorhanden ist und einen Hydroxy-(C1―C6)-alkylrest darstellt, die gestrichelte Linie anzeigt, daß eine Doppelbindung entweder zwischen dem heterocyclischen Stickstoffatom und dem Kohlenstoffatom oder zwischen dem Sauerstoff- und dem Kohlenstoffatom vorhanden ist, wobei im ersten Fall der Rest R4 an das Sauerstoffatom und im zweiten Fall an das Stickstoffatom gebunden ist, oder mit einem Gemisch der beiden Isomeren, in dem R4 die gleiche Bedeutung hat, mit einem molaren Überschuß eines Halogenierungsmittels bei einer Temperatur zwischen Raumtemperatur und etwa 70°C und Umwandlung des erhaltenen Halogenalkyl-Derivates in bekannter Weise in das Aminoalkyl-Derivat.
7. Arzneimittel, enthaltend mindestens eine Verbindung nach Anspruch 1 als Wirkstoff.
8. Eine Verbindung nach Anspruch 1 zur Verwendung als Arzneistoff.
EP83102648A 1982-03-30 1983-03-17 Isoxazole (5,4-b) Pyridine Expired EP0090275B1 (de)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AT83102648T ATE30425T1 (de) 1982-03-30 1983-03-17 Isoxazole (5,4-b) pyridine.

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB8209361 1982-03-30
GB8209361 1982-03-30

Publications (3)

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EP0090275A2 EP0090275A2 (de) 1983-10-05
EP0090275A3 EP0090275A3 (en) 1984-05-02
EP0090275B1 true EP0090275B1 (de) 1987-10-28

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US (1) US4530927A (de)
EP (1) EP0090275B1 (de)
JP (1) JPS58177992A (de)
AT (1) ATE30425T1 (de)
AU (1) AU561013B2 (de)
CA (1) CA1204440A (de)
DE (1) DE3374199D1 (de)
DK (1) DK143583A (de)
ES (1) ES8405407A1 (de)
GR (1) GR77945B (de)
IL (1) IL68171A (de)
PH (1) PH18337A (de)
ZA (1) ZA831738B (de)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7176215B2 (en) 2001-10-16 2007-02-13 Celltech R&D Limited Bicyclic oxopyridine and oxopyrimidine derivatives

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2161667B (en) * 1984-07-12 1988-04-27 John Spencer Liggett Portable facial image synthesiser
JPH04368375A (ja) * 1991-06-17 1992-12-21 Otsuka Pharmaceut Factory Inc イソオキサゾール誘導体
JPH11508539A (ja) * 1995-06-29 1999-07-27 ノボ ノルディスク アクティーゼルスカブ 新規の置換アザ環式化合物
CA2451057A1 (en) * 2001-06-14 2002-12-27 Banyu Pharmaceutical Co., Ltd. Novel isoxazolopyridone derivatives and use thereof

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3381016A (en) * 1966-03-04 1968-04-30 Upjohn Co Isoxazolo[5, 4-b]pyridine derivatives and a method for their preparation
US3541101A (en) * 1966-03-04 1970-11-17 Upjohn Co Isoxazolo(5,4-b)pwridines,5,6 - polymethyleneisoxazolo(5,4 - b)pyridines and processes therefor
US3816429A (en) * 1971-08-10 1974-06-11 Ciba Geigy Corp Tetrahydroisoxazolo(5,4-c)isoquinolines
IT1054655B (it) * 1975-08-27 1981-11-30 Lepetit Spa Derivati condensati del l isochinolina

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7176215B2 (en) 2001-10-16 2007-02-13 Celltech R&D Limited Bicyclic oxopyridine and oxopyrimidine derivatives

Also Published As

Publication number Publication date
ES521083A0 (es) 1984-06-01
DK143583A (da) 1983-10-01
ZA831738B (en) 1984-01-25
EP0090275A2 (de) 1983-10-05
AU561013B2 (en) 1987-04-30
JPH0342276B2 (de) 1991-06-26
IL68171A (en) 1986-03-31
EP0090275A3 (en) 1984-05-02
US4530927A (en) 1985-07-23
JPS58177992A (ja) 1983-10-18
CA1204440A (en) 1986-05-13
ES8405407A1 (es) 1984-06-01
AU1233083A (en) 1983-10-06
ATE30425T1 (de) 1987-11-15
IL68171A0 (en) 1983-06-15
GR77945B (de) 1984-09-25
DK143583D0 (da) 1983-03-29
PH18337A (en) 1985-06-05
DE3374199D1 (de) 1987-12-03

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